The present invention concerns a process for preparing crystalline 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one substantially free of 2-acetylbutyrolactone. This product is a new intermediate for the preparation of 9-hydroxyrisperidone or paliperidone and that of 9-hydroxyrisperidone palmitate ester or paliperidone palmitate ester.
The previously described synthesis of the latter compounds involved the preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one. In EP-0,368,388 (U.S. Pat. No. 5,158,952) this starting material was prepared in situ by reacting 3-phenylmethoxy-pyridin-2-amine with 1.7 equivalents 2-acetyl-butyrolactone (3-acetyl-4,5-dihydro-2(3H)-furanone) in toluene in the presence of phosphoryl chloride, adding another 1.7 equivalents of 2-acetylbutyrolactone after five hours of stirring at 90° C., followed by hydrogenolysis of the benzyl group and concomitant reduction of the pyridine ring to a tetrahydropyridine ring. The resulting 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one was isolated as an oil which allowed further conversion to paliperidone and paliperidone palmitate ester in the laboratory.
During chemical development this process was altered. 2-Amino-3-hydroxypyridine was reacted with 2-acetyl-butyrolactone in the presence of p-toluenesulfonic acid in xylene to yield 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; this product proved to be poorly soluble in xylene resulting in deposit formation on the wall of the reaction vessel and discoloration of the reaction mixture to black.
The intermediate product was subsequently converted into the 2-chloroethyl derivative by reaction with thionyl chloride in dimethylformamide. This reaction was characterized by very severe smell hindrance, probably caused by reaction of residual 2-acetylbutyrolactone remaining from the previous step and nonreproducible yield and quality.
In order to solve the problems described in the previous paragraph, various solvent systems and acids were tested in which to conduct the reaction of 2-amino-3-hydroxypyridine with 2-acetyl-butyrolactone.
The tested solvent systems were:    a) toluene    b) 2-acetylbutyrolactone as solvent and reagent (no co-solvent)    c) propylene glycol monomethyl ether (PGMME)    d) 4-methyl-2-pentanol    e) xylene combined with 4-methyl-2-pentanol    f) dimethylacetamide    g) chlorobenzene    h) acetic acid    i) glyme    j) diglyme
The tested acids were p-toluenesulfonic acid and acetic acid.
The results of the tests can be summarized as follows:    1) Solvent systems:            a) Toluene suffered from the same problems as xylene, namely that the reaction product was very poorly soluble therein and was deposited on the walls of the reaction vessel.        b) Conversion in the absence of a co-solvent varied between 53 and 77%. The process was characterized by excessive foaming.        c) Conversion in PGMME varied from 36 to 67%.        d) Conversion in 4-methyl-2-pentanol varied between 59 and 66%.        e) Conversion in a mixture of xylene and 4-methyl-2-pentanol was about 62%.        f) In dimethylacetamide, the conversion was only 38%.        g) Conversion in chlorobenzene ranged from 55 to 81%, conversion being higher when equimolar amounts of both reagents were used and being lower when excess 2-acetylbutyrolactone was used. Interestingly, the reaction mixture remained homogeneous when chlorobenzene was the solvent.        h) In acetic acid the conversion was only 22%.        i) No conversion in glyme.        j) Diglyme suffered from the same problems as xylene, namely that the reaction product was very poorly soluble therein and was deposited on the walls of the reaction vessel.            2) Acid systems: the conversion was 10% lower for the acetic acid system compared with the p-toluenesulfonic acid system.
Further optimisation of the reaction conditions taught us that optimal results could be obtained by reacting 1 mol equivalent of 2-amino-3-hydroxypyridine with a slight excess (e.g. 1.05 mol equivalent) of 2-acetylbutyrolactone in about 1.75 L/mol equivalent of chlorobenzene in the presence of about 0.03 mol equivalent p-toluene-sulfonic acid monohydrate during 19 hours at 125-135° C. with removal of water using a reverse water separator.
Three different work-up procedures were evaluated next:                k) Cooling the reaction mixture to about 80° C., adding 0.25 L/mol equivalent 2-propanol, reheating to reflux, allowing spontaneous cooling, collecting the resulting crystals,        l) Cooling the reaction mixture and collecting the resulting crystals, and        m) Cooling the reaction mixture to about 80° C., adding 0.25 L/mol equivalent PGMME, reheating to reflux, allowing spontaneous cooling, collecting the resulting crystals.        
In procedure l), the product proved to contain more residual 2-acetylbutyrolactone and 2-amino-3-hydroxypyridine than product obtained in procedures k) and m).
Finally, process k) was further optimised by adding a mixture of activated carbon and filter agent (dicalite speed plus).